Kaposi's sarcoma (KS) is the leading neoplasm afflicting patients with untreated AIDS. Although declining in incidence in the USA since the introduction of highly active antiretroviral therapy, it remains an important clinical problem in both Southern Europe and Africa. KS is an unusual tumor in that (i) it is precipitated by infection with a novel herpesvirus, known as KS-associated herpesvirus (KSHV);and (ii) it is accompanied by striking inflammatory and angiogenic processes, which it induces and on which it appears to depend. The long-term objective of this research is to understand the roles of latent KSHV gene expression in the pathogenesis of KS. In earlier work, through examination of KSHV genes expressed in KS tumors, we identified the kaposin locus, which we and others subsequently found to encode several protein products and a large set of microRNAs expressed in latency. To understand the pathogenetic roles of these numerous products, we now propose two specific aims: 1. Characterization of the biochemical mechanisms by which kaposin proteins act. These studies will focus on (i) the interactions of kaposins B and C with components of the p38-MK2 pathway, and (ii) the identification and characterization of additional host signaling molecules and other factors targeted by kaposins;and 2. Examination of the functions of the KSHV microRNAs generated from latently-expressed kaposin transcripts. These studies will involve strategies that either inactivate the miRNAs or lead to their selective expression. The effects of these manipulations on viral and host gene expression will be assessed by expression profiling using host- and virus-specific DNA microarrrays. Parallel studies will examine the phenotypic consequences of miRNA expression on host cells. Public Health Relevance: KSHV infection of patients with HIV/AIDS leads to the disfiguring tumor known as Kaposi's sarcoma (KS). By determining how viral infection leads to KS, we hope to identify molecular targets that can explain how the disease arises;these could also serve as targets for the therapies of the future.